Sodium nitroprusside is a known infusion preparation for the rapid and controlled lowering of the blood pressure in the case of operations or hypertension crises and for reducing the work load of the heart, e.g. in the case of heart attack. However, it has disadvantages which restrict the use of this valuable and extraordinarily well controllable medicament. Thus, it decomposes in the body very rapidly with the formation of 5 moles of cyanide per molecule. Since cyanide is an acutely toxic agent which blocks the respiratory chain and paralyses the respiratory centre, SNP must be used in order to avoid an accumulation of toxic cyanide concentrations in the blood serum only with the strictest maintenance of prescribed highest dosages and even then only for a short time.
In common with other vasodilators SNP has the disadvantage that the desired rapid and powerful lowering of blood pressure leads very frequently to an activation of the so- called counter-regulation, whereby, in turn, the amount of circulating hormones which increase blood pressure (adrenalin, noradrenalin and angiotensin II) and of renin is greatly increased. This causes, especially in young patients, a strong tendency to increased blood pressure which can be compensated only by successive increase of the dosage of SNP to be infused (tachyphylaxis). If in such cases the administration of SNP is not discontinued, a dangerous increase of the cyanide level in the blood serum can arise very rapidly, even on short-term use of SNP, because of the over-dosage which then occurs. If in this case the tolerance limit of about 0.8 .mu.g of CN/100 ml of blood plasma is exceeded, severe cyanide poisoning and even death can arise (see Anesthesiology 47, 441-448 (1977); Bull. Med. Legale Toxicol. 21, 215-224 (1978); Amer. J. Obstet. Gynecol. 139, 708-711 (1981)).
A further disadvantage of SNP is the appearance of the so-called "rebound" hypertension owing to persistent counter-regulation after termination of the SNP infusion. (New England J Med. 302, 1029-1030 (1980); Anesthesiology 44, 345-348 (1976)). Since this "rebound" hypertension occasionally causes blood pressure levels which lie far above the initial blood pressure, secondary bleedings can occur in newly operated patients and dangerous blood perfusion disorders in the brain owing to oedema formation can occur in predisposed patients.
Since, on the other hand, SNP is at present the most active agent for the controlled lowering of blood pressure, e.g. during operations, attempts have been made to eliminate the mentioned disadvantages.
MacRae has recently proposed (Anaesthesia 36,312-315 (1981)) to infuse SNP together with the ganglionic blocking agent trimethaphan camsylate (TMC). in the weight ratio 1:10. He reported that thereby the amount of SNP required for the same lowering of the blood pressure was considerably lower.
TMC and its blood pressure-lowering activity are known and TMC is therefore employed therapeutically (in spite of its lower activity) similarly to SNP, i.e. as an infusion preparation for the controlled short-term lowering of blood pressure. However, TMC displays, in turn, a series of side effects which restrict its use.
Thus, in addition to such side effects as tachycardia, mydriasis, cycloplegia, urine retention, xerostomia and constipation, which occur by blockade of the parasympathetic ganglia, nausea or vomiting can arise in sensitive patients and, especially in children and aged patients, allergies can arise owing to histamine liberation.
Moreover, trimethaphan camsylate must not be used alone in the case of operations in the region of the gastro-intestinal tract.
The dosage of SNP required for the controlled lowering of blood pressure is on average about 3 .mu.g/kg body weight per minute, that of TMC about 30 .mu.g/kg per minute. Corresponding to this ratio of the pharmacological activities the concentrations of the infusion solutions usually used are thus 0.01 and 0.1%, respectively. The ratio of 1:10 proposed by MacRae (loc. cit.) therefore corresponds to the relative strengths of the two agents.
According to MacRae, the clinical activities of the single components in the 1:10 infusion mixture appear to be additive or even become potentiated, while the corresponding side-effects (because of their qualitative difference) are relatively diminished. Thus, seeing that ad hoc preparation of the mixture in the clinic is complicated and, because of the errors which are possible in practice, even dangerous, it appeared advantageous to develop an appropriate combination product.
However, an obstacle to the development of such a combination product was the fact that the two single drugs are not compatible in concentrated form. When preparing the mixture either drug had firstly to be diluted to infusion strength, and these solutions could then be mixed shortly before the infusion. Because of the limited storage stability of dilute solutions of TMC and SNP and because of the known extreme light sensitivity of SNP solutions, such a highly diluted combination product is, in any event, not suitable as a commercial product.
The observation that the adduct of the two active ions, the hitherto unknown bis-(trimethaphan)-nitroprusside (I), can be isolated in pure form and in high yield and can be processed to a storable pharmaceutical composition was therefore surprising.